The orexin receptor 2 (OX2R)-selective agonist TAK-994 increases wakefulness without affecting cerebrospinal fluid orexin levels in cynomolgus monkeys

Abstract

Orexin A (OX-A) and orexin B are neuropeptides produced in orexin neurons located in the lateral hypothalamus that exert multiple biological functions through the activation of orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R) throughout the central nervous system. OX1R and OX2R have distinct functions: OX1R is involved in reward seeking, whereas OX2R has a pivotal role in sleep/wake regulation. OX2R-selective agonists are in development as novel therapeutic agents for the treatment of hypersomnia. However, their potential to induce orexin release, which may indirectly stimulate both OX1R and OX2R in vivo, is unclear. Herein, we assessed the effects of the OX2R-selective agonist TAK-994 on wakefulness and orexin release in monkeys. Oral administration of TAK-994 at 10 mg/kg in the beginning of the sleep phase (zeitgeber time [ZT] 12) significantly increased wakefulness time in monkeys but did not increase OX-A levels in monkey cisternal cerebrospinal fluid (CSF). Moreover, oral administration of TAK-994 (10 mg/kg) during the active phase (ZT1) did not increase OX-A levels in monkey CSF. These findings indicate that the OX2R agonist TAK-994 selectively activates OX2R in vivo and would not robustly induce spontaneous orexin release during the daytime or nighttime in monkeys.